Diabetes insipidus pathophysiology: Difference between revisions

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Revision as of 21:33, 12 July 2017

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Pathogenesis

Central Diabetes insipidus

The posterior pituitary consists of paraventricular and the supra-optic nuclei that synthesizes oxytocin and arginine vasopressin respectively. The axons of these hormones project to the neurohypophysis where the hormones are secreted into the blood stream to allow maximum antidiuresis for 5–10 days. The maintenance of water balance in healthy humans is achieved principally by three interrelated determinants:

Thirst
AVP
Kidney function

AVP acts on the kidney, where it increases urine osmolality. It binds to the V2-receptors in the basolateral membrane of the renal collecting tube and activates the Gs-adenyl cyclase system, increasing intracellular levels of cyclic 3′,5′-adenosine monophosphate (cAMP) activating protein kinase A, which in turn phosphorylates preformed AQP2 water channels localized in intracellular vesicles.^[1]

Nephrogenic diabetes insipidus

In nephrogenic DI, solute excretion and all filtration functions of the kidney are normal but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of endogenous vasopressin. Abnormalities in the medullary osmotic gradient directed by antidiuretic hormone (ADH) or arginine vasopressin (AVP) and inhibition of the action of ADH on the renal tubules are both thought to be mechanisms of development of nephrogenic DI. The lack of response to ADH is due to the inhibition of adenylate cyclase and resultant decreased formation of cyclic cAMP. cAMP serves as a second messenger to protein kinase A and the fusion of aquaporin storage vesicles to the luminal cell wall, which in turn allows the collecting ducts to become permeable and reabsorb water.

Genetics

More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of AVP have been identified in familial central diabetes.^[2]^[3]
Majority have an autosomal dominant form of inheritance

Associated Conditions

Sickle cell disease
Amyloidosis,
Obstructive uropathy
Electrolyte disorders (e.g.,hypokalemia and hypercalcemia),
Pregnancy
Conditions induced by a drug (e.g., lithium, demeclocycline, Amphotericin B and

vincristine)

Lithium is the most common cause of drug-induced nephrogenic DI

Gross Pathology

Microscopic Pathology

References

↑ Agre P (2004). "Nobel Lecture. Aquaporin water channels". Biosci Rep. 24 (3): 127–63. PMID 16209125.
↑ Christensen, Jane H.; Rittig, Søren (2006). "Familial Neurohypophyseal Diabetes Insipidus—An Update". Seminars in Nephrology. 26 (3): 209–223. doi:10.1016/j.semnephrol.2006.03.003. ISSN 0270-9295.
↑ Ghirardello, S.; Garrè, M.-L.; Rossi, A.; Maghnie, M. (2007). "The Diagnosis of Children with Central Diabetes Insipidus". Journal of Pediatric Endocrinology and Metabolism. 20 (3). doi:10.1515/JPEM.2007.20.3.359. ISSN 2191-0251.

Template:WH Template:WS

[pmid16209125-1] Agre P (2004). "Nobel Lecture. Aquaporin water channels". Biosci Rep. 24 (3): 127–63. PMID 16209125.

[ChristensenRittig2006-2] Christensen, Jane H.; Rittig, Søren (2006). "Familial Neurohypophyseal Diabetes Insipidus—An Update". Seminars in Nephrology. 26 (3): 209–223. doi:10.1016/j.semnephrol.2006.03.003. ISSN 0270-9295.

[GhirardelloGarrè2007-3] Ghirardello, S.; Garrè, M.-L.; Rossi, A.; Maghnie, M. (2007). "The Diagnosis of Children with Central Diabetes Insipidus". Journal of Pediatric Endocrinology and Metabolism. 20 (3). doi:10.1515/JPEM.2007.20.3.359. ISSN 2191-0251.

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@@ Line 28: / Line 28: @@
 *Conditions  induced  by  a  drug  (e.g.,  lithium, demeclocycline, Amphotericin       B       and
 vincristine)
-*Lithium  is  the  most  common
+*Lithium  is  the  most  common cause of drug-induced nephrogenic DI
-cause of drug-induced nephrogenic DI
 ==Gross Pathology==
 ==Microscopic Pathology==
-* [[Diabetes Insipidus|Diabetes insipidus]] (DI) is an endocrine disorder involving deficient production or lack of effective action of pituitary antidiuretic hormone (ADH, AVP, arginine vaopressin)
+*
-* DI is characterized by chronic excretion of very large amounts of urine
-* DI is coupled with [[Ddx:Dehydration|dehydration]] and excessive thirst
-Electrolyte and volume [[homeostasis]] is a complex mechanism that balances the body's requirements for [[blood pressure]] and the main electrolytes [[sodium]] and [[potassium]]. In general, electrolyte regulation precedes volume regulation. When the volume is severely depleted, however, the body will retain water at the expense of deranging electrolyte levels.
-The regulation of urine production occurs in the [[hypothalamus]], which produces [[antidiuretic hormone]] (ADH or vasopressin) in the [[Supraoptic nucleus|supraoptic]] and [[Paraventricular nucleus|paraventricular]] nuclei.  After synthesis, the hormone is transported in neurosecretory granules down the axon of the hypothalamic neuron to the posterior lobe of the [[pituitary gland]] where it is stored for later release. In addition, the hypothalamus regulates the sensation of thirst in the [[ventromedial nucleus]] by sensing increases in serum osmolarity and relaying this information to the [[Cerebral cortex|cortex]].
-The main effector organ for [[body water|fluid]] homeostasis is the [[kidney]]. ADH acts by increasing water permeability in the [[collecting ducts]], specifically it acts on proteins called [[aquaporin]]s which open to allow water into the collecting duct cells. This increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating the urine.
-There are several forms of DI:
-* ''Central'' diabetes insipidus is due to damage to the hypothalamus or pituitary due to a [[tumor]], [[cerebrovascular accident|stroke]], [[neurosurgery]] or some rather rare causes (which include [[hemochromatosis]], [[sarcoidosis]], [[histiocytosis]], diseases that can form masses in the vicinity like a [[tuberculoma]] or [[syphilis]] and some [[genetic disorder]]s). If the hypothalamus is damaged, the feeling of thirst may be completely absent.
-* ''Nephrogenic'' diabetes insipidus is due to the inability of the kidney to respond normally to ADH. There are hereditary causes (90% are due to mutations of the ADH V2 receptor, and 10% mutations of the [[aquaporin#AQP2|aquaporin 2]] water channel), but these are rare (incidence is around 4 per million live births). Most are male, because V2 receptor mutations are x-linked recessive defects. More common are acquired forms of NDI, which occur as a side-effect to some [[medication]]s (such as [[lithium citrate]] and [[amphotericin B]]), as well as in [[polycystic kidney disease]] (PKD) and [[sickle-cell disease]], and electrolyte disturbances such as hypokalaemia and hypercalcaemia. In some cases, no cause is found.
-* ''Dipsogenic'' DI is due to a defect or damage to the thirst mechanism, which is located in the hypothalamus. This defect results in an abnormal increase in thirst and fluid intake that suppresses ADH secretion and increases urine output. Desmopressin is ineffective, and can lead to fluid overload as the thirst remains.
-* ''Gestational'' DI only occurs during [[pregnancy]]. While all pregnant women produce ''vasopressinase'' in the [[placenta]], which breaks down ADH, this can assume extreme forms in GDI. Most cases of gestational DI can be treated with desmopressin. In rare cases, however, an abnormality in the thirst mechanism causes gestational DI, and [[desmopressin]] should not be used.
 ==References==
 {{reflist|2}}